The present invention relates to biphenyl derivatives of general formula 
their isomers, their salts, particularly the physiologically acceptable salts thereof which have valuable pharmacological properties.
The compounds of the above general formula I are valuable inhibitors of the microsomal triglyceride-transfer protein (MTP) and are therefore suitable for lowering the plasma level of the atherogenic lipoproteins.
In the above general formula I
n denotes the number 1, 2, 3, 4 or 5,
Ra and Rb, which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom, a C1-3-alkyl group wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms, a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
Rc denotes a hydrogen atom,
a C1-10-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl group, wherein in each case the hydrogen atoms may be wholly or partially replaced by fluorine atoms,
a phenyl, naphthyl or monocyclic 5 or 6-membered heteroaryl group optionally substituted by a fluorine, chlorine or bromine atom, by a C1-3-alkyl group wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms, by a hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or N,N-di-(C1-3-alkyl)-aminocarbonyl group, by a 3- to 7-membered cycloalkyleneimino group, wherein the methylene group in the 4 position in a 6- or 7-membered cycloalkyleneimino group may additionally be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N-(C1-3-alkyl)-imino group, by a nitro, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-3-alkylcarbonylamino, N-(C1-3-alkyl)-C1-3-alkylcarbonylamino, C1-3-alkylsulphonylamino or N-(C1-3-alkyl)-C1-3-alkylsulphonylamino group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl group, an oxygen or sulphur atom, or an imino group optionally substituted by a C1-3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms, and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms,
Rd denotes a phenyl, naphthyl or monocyclic 5 or 6-membered heteroaryl group optionally substituted by a fluorine, chlorine or bromine atom, by a C1-3-alkyl group wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms, by a hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or N,N-di-(C1-3-alkyl)-aminocarbonyl group, by a 3- to 7-membered cycloalkyleneimino group, wherein the methylene group may additionally be replaced in the 4 position in a 6-or 7-membered cycloalkyleneimino group by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N-(C1-3-alkyl)-imino group, by a nitro, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-3-alkylcarbonylamino, N-(C1-3-alkyl)-C1-3-alkylcarbonylamino, C1-3-alkylsulphonylamino or N-(C1-3-alkyl)-C1-3-alkylsulphonylamino group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl group, an oxygen or sulphur atom, or an imino group optionally substituted by a C1-3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms, and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms,
Re denotes a carboxy group, a C1-6-alkoxycarbonyl or C3-7-cycloalkoxycarbonyl group wherein the alkyl or cycloalkyl moiety may be substituted in each case from the 2 position, relative to the oxygen atom, by a C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, a phenyl-C1-3-alkoxycarbonyl or heteroaryl-C1-3-alkoxycarbonyl group, while the heteroaryl moiety is as hereinbefore defined,
Rf denotes a hydrogen atom, a C1-3-alkyl or phenyl-C1-3-alkyl group and
Rg denotes a hydrogen atom or a C1-3-alkyl group.
However, preferred compounds of the above general formula I are those wherein
Rb to Rg are as hereinbefore defined and
Ra is in the 3xe2x80x2 or 4xe2x80x2 position and has the meanings given hereinbefore with the exception of the hydrogen atom,
the isomers and salts thereof.
However, particularly preferred compounds of the above general formula I are those wherein
n denotes the number 3, 4 or 5,
Ra denotes a hydrogen, fluorine, chlorine or bromine atom, a C1-3-alkyl, trifluoromethyl or C1-3-alkoxy group,
Rb denotes a hydrogen, fluorine, chlorine or bromine atom,
Rc denotes a C1-5-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl group or
a phenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C1-3-alkyl group,
Rd denotes a phenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C1-3-alkyl group,
Re denotes a carboxy group, a C1-6-alkoxycarbonyl or C3-7-cycloalkoxycarbonyl group wherein the alkyl or cycloalkyl moiety may be substituted in each case from the 2 position, relative to the oxygen atom, by a C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, a phenyl-C1-3-alkoxycarbonyl, pyridyl-C1-3-alkoxycarbonyl or pyrimidyl-C1-3-alkoxycarbonyl group,
Rf denotes a hydrogen atom or a C1-3-alkyl group and
Rg denotes a hydrogen atom or a C1-3-alkyl group,
the isomers and salts thereof.
The following are mentioned as examples of particularly valuable compounds:
(a) methyl 2-methyl-2-phenyl-5-{4-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-piperidin-1-yl}-pentanecarboxylate,
(b) methyl 2-ethyl-2-phenyl-5-{4-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-piperidin-1-yl}-pentanecarboxylate and
(c) methyl 2-methyl-2-phenyl-6-{4-[(4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl)-amino]-piperidin-1-yl}-hexanecarboxylate.
According to the invention, the new compounds are obtained by methods known from the literature, for example by the following methods:
a. reacting a compound of general formula 
wherein
Ra, Rb, Rf and Rg are as hereinbefore defined, with a compound of general formula 
wherein
n and Rc to Re are as hereinbefore defined and
Z1 denotes a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a p-nitrophenyl group.
The reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone/water, dimethylformamide or dimethylsulphoxide optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tert-butoxide or N-ethyl-diisopropylamine at temperatures between 0 and 100xc2x0 C., preferably at temperatures between 10 and 60xc2x0 C.
b. In order to prepare a compound of general formula I, wherein Re has the meanings given hereinbefore for Re with the exception of the carboxy group:
esterifying a compound of general formula 
wherein
n, Ra to Rd, Rf and Rg are as hereinbefore defined, or the reactive derivatives thereof with an alcohol of general formula
Hxe2x80x94Rexe2x80x2, xe2x80x83xe2x80x83(V)
wherein
Rexe2x80x2 denotes a C1-6-alkoxy or C3-7-cycloalkoxy group wherein the alkyl or cycloalkyl moiety may be substituted in each case from the 2 position, relative to the oxygen atom, by a C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, a phenyl-C1-3-alkoxy or heteroaryl-C1-3-alkoxy group, while the heteroaryl moiety is as hereinbefore defined, or, in order to prepare a tert-butyl ester, 2,2-dimethyl-ethene, in the presence of an acid.
The reaction is optionally carried out in the presence of a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, but preferably in an excess of the alcohol of general formula V used as solvent, optionally in the presence of an acid such as hydrochloric acid or sulphuric acid or in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexyl-carbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxy-succinimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1 H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine, appropriately at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 100xc2x0 C.
The reaction of a corresponding reactive compound of general formula IV such as the esters, imidazolides or halides with an alcohol of general formula V is preferably carried out in a corresponding alcohol as solvent, optionally in the presence of another solvent such as methylene chloride or ether and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 50 and 100xc2x0 C.
The formation of the tert.butyl ester with 2,2-dimethyl-ethene is preferably carried out in a solvent such as diethyl ether, dioxane, methylene chloride or tert.butanol in the presence of an acid such as sulphuric acid, hydrochloric acid or boron fluoride-diethyletherate at temperatures between xe2x88x9220 and 150xc2x0 C., preferably at temperatures between 0 and 100xc2x0 C.
c. In order to prepare a compound of general formula I wherein Re denotes a carboxy group:
converting a compound of general formula 
wherein
n, Ra to Rd, Rf and Rg are as hereinbefore defined and
Rexe2x80x3 denotes a group which can be converted into a carboxy group, into a compound of general formula I wherein Re denotes a carboxy group.
The group which may be converted into a carboxy group may be, for example, a carboxyl group protected by a protecting group, such as the functional derivatives thereof, e.g. the unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or iminoesters thereof, which may expediently be converted by hydrolysis into a carboxyl group,
the esters thereof with tertiary alcohols, e.g. the tert. butyl ester, which are expediently converted into a carboxyl group by treating with an acid or thermolysis, and
the esters thereof with aralkanols, e.g. the benzyl ester, which are expediently converted into a carboxyl group by hydrogenolysis.
The hydrolysis is expediently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures between xe2x88x9210 and 120xc2x0 C., e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
If Rexe2x80x3 in a compound of formula VI denotes the tert. butyloxycarbonyl group, for example, this may also be cleaved by treating with an acid such as trifluoroacetic acid, formic acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane preferably at temperatures between xe2x88x9210 and 120xc2x0 C., e.g. at temperatures between 0 and 60xc2x0 C., or thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40 and 120xc2x0 C.
If Rexe2x80x3 in a compound of formula VI denotes the benzyloxycarbonyl group, for example, this may also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50xc2x0 C., e.g. at ambient temperature, and at a hydrogen pressure of 1 to 5 bar.
If according to the invention a compound of general formula I is obtained which contains a nitro group it may be converted by reduction into a corresponding amino compound, or if a compound of general formula I is obtained wherein Rf denotes a hydrogen atom, it may be converted by alkylation into a corresponding compound wherein Rf denotes a C1-3-alkyl or phenyl-C1-3-alkyl group.
The subsequent reduction of a nitro group is expediently carried out hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as platinum, palladium/charcoal or Raney nickel in a suitable solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dimethylformamide or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid and at a hydrogen pressure of 1 to 7 bar, but preferably 1 to 5 bar, with metals such as iron, tin or zinc in the presence of an acid such as acetic acid or hydrochloric acid, with salts such as iron(II)sulphate, tin (II) chloride, sodium sulphide, sodium hydrogen sulphite or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 100xc2x0 C., but preferably at temperatures between 20 and 60xc2x0 C.
The subsequent alkylation is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, dioxane, dimethylsulphoxide or sulpholane with an alkylating agent such as a corresponding halide or sulphonic acid ester, e.g. with methyl iodide, ethyl bromide, dimethyl sulphate or benzyl chloride, optionally in the presence of a tertiary organic base or in the presence of an inorganic base, conveniently at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 100xc2x0 C., or by reductive alkylation.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl, tert.butyl-dimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,
a protecting group for a carboxyl group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and
protecting groups for an amino, alkylamino or imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120xc2x0 C., preferably at temperatures between 10 and 100xc2x0 C. However, a silyl group may also be cleaved using tetrabutylammonium fluoride as described hereinbefore.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved for example hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100xc2x0 C., but preferably at temperatures between 20 and 60xc2x0 C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120xc2x0 C. or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50xc2x0 C.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50xc2x0 C.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in xe2x80x9cTopics in Stereochemistryxe2x80x9d, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (xe2x88x92)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (xe2x88x92)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
Moreover, if the new compounds of formula I thus obtained contain an acidic group such as a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The compounds of general formulae II to VI used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature or are described in the Examples. Thus, for example, a compound of general formula III is obtained by esterifying a corresponding disubstituted carboxylic acid and subsequently reacting with an xcex1,xcfx89-dihaloalkane in the presence of a strong base such as lithium diisopropylamide, sodium amide or sodium hydride.
As already mentioned hereinbefore, the compounds of general formula I and the physiologically acceptable salts thereof have valuable pharmacological properties. In particular, they are valuable inhibitors of the microsomal triglyceride-transfer protein (MTP) and are therefore suitable for lowering the plasma levels of the atherogenic lipoproteins.
For example, the compounds according to the invention were investigated for their biological effects as follows:
Inhibitors of MTP were identified by a commercially obtainable MTP activity kit(WAK-Chemie Medical GmbH, Sulzbacherstrasse 15-21, D-65812 Bad Soden, Germany). This test kit contains donor and acceptor particles. The donor particles contain fluorescence-labelled triglycerides in a concentration high enough to cause self-extinction of the fluorescence. When the donor and acceptor particles were incubated with an MTP source, fluorescence-labelled triglycerides were transferred from the donor to the acceptor particles. This led to an increase in the fluorescence in the sample. Solubilised liver microsomes from various species (e.g. rat) could be used as the MTP source. Inhibitors of MTP were identified as the substances which reduced the transfer of fluorescence-labelled triglycerides compared with a control mixture with no inhibitor.
In view of the abovementioned biological properties the compounds of general formula I and the physiologically acceptable salts thereof are particularly suitable for lowering the plasma concentration of atherogenic apolipoprotein B (apoB)-containing lipoproteins such as chylomicrons and/or very low density lipoproteins (VLDL) as well as the residues thereof such as low density lipoproteins (LDL) and/or lipoprotein(a) (Lp(a)), for treating hyperlipidaemias, for preventing and treating atherosclerosis and the clinical sequelae thereof, and for preventing and treating related disorders such as diabetes mellitus, adiposity and pancreatitis, oral administration being preferred.
The daily dose needed to achieve such an effect is between 0.5 and 500 mg, expediently between 1 and 350 mg, but preferably between 5 and 200 mg, in adults.
For this purpose, the compounds of formula I prepared according to the invention, optionally combined with other active substances such as other lipid-lowering agents, for example HMG-CoA-reductase inhibitors, cholesterol biosynthesis inhibitors such as squalene synthase inhibitors and squalene cyclase inhibitors, bile acid-binding resins, fibrates, cholesterol resorption inhibitors, niacin, probucol, CETP inhibitors and ACAT inhibitors may be incorporated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.